Itch, or pruritus, is an unpleasant cutaneous sensation that evokes scratching behavior, which is distinct from pain that elicits withdrawal reflex of affected body (1). Like pain, itch serves as a self-protective and warning system in normal conditions (1). Under pathological conditions, such as dermatitis, liver or kidney diseases and metabolic disorders, itch becomes persistent, recurrent and intractable (2-5). Although itch is transiently relieved by scratching, itch-scratch cycles often results in further skin damage that exacerbates the problem (6). Antihistamines are normally used for itch relief, but many chronic itchy conditions are resistant to antihistamine treatment (7).
Although itch and pain share many similarities (1; 7; 8), increasing evidence points to distinct molecular mechanisms of itch (9-12). Primary sensory neurons located in trigeminal ganglion and dorsal root ganglion (DRG) are responsible for transducing itch stimuli to the central nervous system (1; 7). As the best-characterized itch mediator, histamine is released from mast cells and binds H1/H4 receptors on skin nerve terminals to elicit itch (13), via activation the PLCbeta3 and transient receptor potential subtype V1 (TRPV1)(14-16). Chloroquine, an anti-malaria drug and also an agonist of sensory neuron-specific G-protein-coupled receptor (GPCR) MrgprA3 and BAMS-22, an endogenous agonist of MrgprC11, can produce histamine-independent itch, in a TRPA1-dependent manner (11; 17). Both histamine-dependent and independent itch require the TRPV1-expressing nociceptors (15; 18). Recent studies showed that loss of vesicular glutamate transporter-2 (vGLUT2) in nociceptors lead to reduced pain but enhanced itch, indicating that glutamate release from these nociceptors is dispensable for signaling itch (19; 20). At the spinal cord level, gastrin releasing peptide (GRP), released from TRPV1-expressing nociceptors, activate GRP receptor (GRPR)-expressing neurons in the laminae I-II to elicit itching sensation (9; 10). Moreover, loss of Bhlhb5-expressing inhibitory interneurons in the spinal cord results in enhanced itch, providing evidence of central sensitization-initiated itch (21).